Abstract Intense acute stress or prolonged stress that overwhelms the body's stress response (SR) system is detrimental to an organism's health and associated with the onset or aggravation of a broad spectrum of health outcomes, including psychiatric disorders. To devise effective therapeutic strategies for stress-aggravated disorders, it is essential to advance our understanding regarding the pathways and genes that regulate our body's response to stress. The prevailing thought is that glucocorticoids, like cortisol or corticosterone, primarily act through genomic actions of their cognate receptors, mineralocorticoid (MR) and glucocorticoid receptors (GR), by effecting transcription. However, appreciation of the role glucocorticoids play in rapid non-genomic responses has led to a push to better understand how these non-genomic responses contribute to stress responses, overall stress system regulation, and contributions to health and disease. Identifying and studying gene products that regulate or modify rapid, non-genomic stress responses will significantly impact our understanding of how SR regulation contributes to health, potentially providing new diagnostics and therapeutics to protect against or treat disease. Zebrafish are genetically tractable vertebrates with conserved SR signaling pathways?a combination of properties that make them an ideal model for discovering genetic modifiers of vertebrate- specific SR signaling. In this proposal we intend to clarify the contribution of key regulators of SR signaling, looking at their role in rapid non-genomic signaling as well as their potential to influence development of the SR in vertebrates. We will also follow up on the discovery of novel genes linked to rapid stress responsive behaviors and use a unique resource of zebrafish mutants to discover more genes that influence the vertebrate SR.